Oral squamous cell carcinoma (OSCC) is an epithelial malignancy of the mucosal lining of the oral cavity. A subpopulation of cells within these tumors is endowed with the ability to initiate tumors (and are, hence, called cancer-initiating cells). These cells have been shown to be more resistant to chemotherapy and radiation than the other cells within the tumor. Thus, the goal of this project is to identify strategies to target these cancer-initiating cells. Here, we will characterize the functional role f a novel marker of oral cancer-initiating cells that we have identified. This molecule, called CD271 (also known as, p75NTR and nerve growth factor receptor) marks the principle cancer-initiating subset of cells in OSCC. Importantly, loss-of- function of this molecule inhibits the tumorigenic phenotype, indicating that it is a functional molecule. We will characterize the ligands and co-receptors that bind CD271, and we will study the signaling that occurs through this receptor and the functional downstream effects upon receptor ligand binding. We will also assess the role of CD271 in managing oxidative stress and radiation resistance. These studies will provide insight as we assess the potential of targeting CD271 therapeutically. Finally, we wil use the expression of CD271 to help dissect the heterogeneity among bulk cells within primary OSCC tumor cells and within normal oral mucosa to elucidate the molecular regulation of differentiation from the oral epithelial progenitor cells.